Dialkylation of CF2 unit enabled by cobalt electron-shuttle catalysis

Abstract

The incorporation of difluoromethylene (CF₂) group into chemical molecules often imparts desirable properties such as lipophilicity, binding affinity, and thermal stability. Consequently, the increasing demand for gem-difluoroalkylated compounds in drug discovery and materials science has continued to drive the development of practical methods for their synthesis. However, traditional synthetic methods such as deoxofluorination often confront challenges including complicated substrate synthesis sequences and poor functional group compatibility. In this context, we herein report a metal electron-shuttle catalyzed, modular synthetic methodology for difluoroalkylated compounds by assembling two C(sp³) fragments across CF₂ unit in a single step. The approach harnesses a difluoromethylene synthon as a biradical linchpin, achieving the construction of two C(sp³)-CF₂ bonds through radical addition to two different π-unsaturated molecules. This catalytic protocol is compatible with broad range of coupling partners including diverse olefins, iminiums, and hydrazones, supporting endeavors in the efficient construction of C(sp³)-rich difluoroalkylated molecules.

Fig. 1. Synthesis of difluoroalkylated compounds.

a Bioisostere design and examples of bioactive molecules containing CF₂ moiety. b State-of-art on the synthesis of difluoroalkylated compounds. c Reaction design using CF₂ biradical linchpin to synthesize difluoroalkylated compounds. d Radical addition tendency according to polarity matching. e This work: dialkylation of CF₂ unit enabled by metal electron-shuttle catalysis. EWG electron-withdrawing group, Ar aryl, DPPBz 1,2-bis(diphenylphosphanyl)benzene.

Fig. 2. Scope of olefins, migrating groups and amines.

a Conditions: alkene S1 (0.30 mmol), bromodifluoromethyl sulfone S2 (0.45 mmol), N,O-acetal S3 (0.45 mmol) in CH₃CN (3.0 mL), 40 °C, 12 h, under nitrogen atmosphere. b Conditions: alkene S1-37 (0.30 mmol), bromodifluoromethyl sulfone S2-1 (0.45 mmol), amine (0.45 mmol), paraformaldehyde (0.60 mmol) in CH₃CN (3.0 mL), 40 °C, 12 h, under nitrogen atmosphere. Isolated yields after chromatography are given. Ar refers to benzothiazolyl group. DPPBz 1,2-bis(diphenylphosphanyl)benzene, Ts tosyl, Me methyl, Bn benzyl, OMe methoxy, Boc tert-butyloxycarbonyl, PMB p-methoxybenzyl, ⁱPr isopropyl, Ph phenyl.

Fig. 3. Scope of hydrazones.

Conditions: alkene S1-37 (0.30 mmol), bromodifluoromethyl sulfone S2-1 (0.45 mmol), hydrazine S5 (0.45 mmol), aldehyde S6 (0.45 mmol) in CH₃CN (3.0 mL), 40 °C, 12 h, under nitrogen atmosphere. Isolated yields after chromatography are given. Ar refers to benzothiazolyl group. DPPBz 1,2-bis(diphenylphosphanyl)benzene, Me methyl, Bz Benzoyl, Boc tert-butyloxycarbonyl, TMS trimethylsilyl, Ph phenyl.

Fig. 4. Scope of electron-deficient olefins.

Conditions: alkene S1-37 (0.30 mmol), bromodifluoromethyl sulfone S2-1 (0.45 mmol), electron-deficient olefin S7 (0.45 mmol) in CH₃CN (3.0 mL), 40 °C, 12 h, under nitrogen atmosphere. Isolated yields after chromatography are given. Ar refers to benzothiazolyl group. DPPBz 1,2-bis(diphenylphosphanyl)benzene, EWG electron-withdrawing group, PhSO₂ benzenesulfonyl, Me methyl, Boc tert-butyloxycarbonyl, Ph phenyl.

Fig. 5. Mechanistic investigations.

a EPR spin-trapping experiments with experimental spectra and simulation. b Radical ring-closing experiment under standard conditions. c Radical ring-opening experiment under standard conditions. d Reactions with excess electron-deficient or electron-rich alkenes. e Proposed reaction mechanism. Ar refers to benzothiazolyl group. PBN N-tert-butyl-α-phenylnitrone, Me methyl, Boc tert-butyloxycarbonyl, PMB p-methoxybenzyl.

Fig. 6. Synthetic transformations.

a Transformations of the difluoroalkylated product 1. b Transformations of the difluoroalkylated product 109. Ar refers to benzothiazolyl group. AIBN azobisisobutyronitrile, (TMS)₃SiH trimethylsilane, Ts tosyl, Ph phenyl.